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Lung Cancer. R. Zenhäusern. Lung cancer: Epidemiology. Most common cancer in the world 2./ 3. most cancer in men / women 1.2 million new cases / year 1.1 million deaths / year Incidence Men 1940-80: 10  70/100000/J Women 1965-: 5  30/100000/J. Lung cancer: Epidemiology.

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Lung cancer l.jpg

Lung Cancer

R. Zenhäusern


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Lung cancer: Epidemiology

  • Most common cancer in the world

    • 2./ 3. most cancer in men / women

  • 1.2 million new cases / year

  • 1.1 million deaths / year

  • Incidence

    • Men 1940-80: 10  70/100000/J

    • Women 1965-: 5  30/100000/J


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Lung cancer: Epidemiology

  • 13% of cancers,

  • 18% of cancer deaths

  • Switzerland 3500 new cases / year

  • 80% die during the first year

  • Prognosis remains dismal:

    • five-year survival 10-14%


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Non-Small-Cell Lung Cancer

  • 75 % of all lung cancers

  • Majority of patients present with stage III and IV


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NSCLC: Histology

  • Squamos-cell carcinoma 20-25%

  • Adenocarcinoma 40%

  • Large cell carcinoma 10%


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NSCLC: Staging

  • Staging Locoregional Disease:

    • Chest x-ray and chest CT scan

      (including liver and adrenal glands)

    • No evidence of distant metastatic disease: FDG-PET ist recommended

    • Biopsy of mediastinal LN ist recommended:

      CT-scan > 1.0 cm or positive on PET

      neg. PET scanning does not preclude biopsy

      ASCO Guideline 2004;22:330


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NSCLC: Staging

  • Staging Distant Metastatic Disease:

    • No evidence of distant metastatic disease on CT scan of the chest: PET ist recommended

    • A bone scan is optional

    • Resectable primary lung lesion and bone lesion on PET/bone scan: MRI/CT and biopsy

    • Brain: CT or MRI if symptoms, patients with stage III considered for aggressive local Th.

    • Isolated adrenal mass: biopsy

    • Isolated liver mass: biopsy

      ASCO Guideline 2004;22:330



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Local NSCLC: Stage I, II

  • Standard of care = Surgery

  • Relapse rate 35%-50% in St. I

  • Relapse rate 40%-60% in St. II

  • Adjuvant radiotherapy ?

  • Adjuvant chemotherapy ?


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Adjuvant Radiotherapy

  • Port meta-analysis Trialist Group. Lancet 1998;352:257

    • 9 randomised trials of postoperative RT versus surgery

      (2128 patients)

    • 21% relative increase in the risk of death with RT

    • Reduction of OS from 55% to 48% (at 2 years)

    • Adverse effect was greatest for Stage I,II

    • St.III (N2): no clear evidence of an adverse effect


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Adjuvant Radiotherapy

  • Conclusion

    • Postoperative RT should not be used outside of a clinical trial in Stage I, II lung cancer, unless surgical margins are positive and repeated resection is not feasible.


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Adjuvant Chemotherapy

  • Undetectable microscopic metastasis at diagnosis

  • Individual trials have not shown a significant benefit

  • Meta-analysis BMJ 1995;311:899:

    • Alkylating agents had an adverse effect

    • Cisplatin-based therapy:

      13% reduction in risk of death (not significant)


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Postoperative Chemo- and Radiotherapy

  • ECOG-Trial: 488 patients with stage II, IIIA

  • RT alone (50.4 Gy) versus

    RT + 4x Cisplatin/Etoposid

  • Median survival 39 vs 38 months (ns)

  • TRM 1.2 vs 1.6%

  • Local recurrence 13 vs 12%

    Keller et al. NEJM 2000;343:1217


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Cisplatin-based Adjuvant Chemotherapy(International Adjuvant Lung Cancer Trial Collaboratvie Group)

  • Randomised trial of 3-4 cycles of cisplatin-based CT vs observation in patients with St. II, III LC

    CT no CT

    5-Y. DFS 39.4% 34.3% p <0.03

    5-y. OS 44.5% 40.4%p <0.03

    IALT. NEJM 2004;350:351


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Overall Survival (Panel A) and Disease-free Survival (Panel B)

The International Adjuvant Lung Cancer Trial Collaborative Group, N Engl J Med 2004;350:351-360


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Adjuvant Chemotherapy B)

  • Conclusion:

    • One should consider the use of adjuvant platinum-based chemotherapy in patients with stage I,II or IIA NSCLC


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Locally advanced NSCLC B)

  • Thoracic irradiation is the mainstay of treatment for inoperable stage III disease

  • Its curative potential is extremely poor

    5-year survival rates 3-5%


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Locally advanced NSCLC B)

  • A meta-analysis of 22 randomised studies showed a beneficial effect of CT added to RT

    • 10% reduction in risk of death per year

    • Small absolute survival benefit:

      4% after 2 years

      2% after 5 years

      NSCLC Collaborative Group. BMJ 1995;311:899


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Combined B)chemotherapy and radiation

  • Sequential strategies

    • Primary CT C C.. R R R R R

    • Primary and adjuvant CT C C.. R R R R R C C

  • Concomitant Strategies

    • Daily CT C C C C C C C C C C

      R R R R R R R R R R

    • Intermittent CT C.. C..

      R R R R R R R R R R

  • Combined Strategies

    • Primary and concomitant CT C...

      C C.. R R R R R


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Sequential CT–RT B)

+ CT in standard dose

 of micrometastasis

 volume of primary tumor

- longer treatment time

delay of RT

Concomittant C-RT

+Improvement of local control

(radiosensitisation)

- greater toxic effects

Reduced dose of CT

Therapeutic Strategies


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Sequential chemo- and radiotherapy B)

  • Studies performed in the 1980s did not show an advantage

  • Three large phase III trials gave pos. Results

    • Dillman etal. NEJM 1990;329:940

    • Sause et al. JNCI 1995;87:198

    • Le Chevalier et al. JNCI 1992;8:58


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Sequential chemo- and radiotherapy B)

Dillman etal. NEJM 1990;329:940 (CALGB 8433)

2 cycles of Cis / Vbl  RT (60 Gy/6 w)

R

RT (60 Gy/6 w)


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Results: Sequential CT and RT B)

Med. S 2y-S 3y-S 7y-S (%)

CT-RT 14 mo 26 23 17

RT 10 mo 13 11 6

Dillman etal. NEJM 1990;329:940

Dillman et al. JNCI 1996;88:1210


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Results: Sequential CT and RT B)

  • US intergroup trialSause W. JNCI 1995;87:198

    n=458Sause W. Chest 2000;117:351

    MS (mo) 5y-S (%)

    RT 11.4 5

    2x Cis/Vbl 13.2 8

    hyper RT 12 6

  • French trialLe Chevalier JNCI 1992;8:58

    N=353

    3x CT  RT vs RT 3y-S 12% vs 4%


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Simultaneous CT / RT is beneficial in: B)

Head and neck cancer

Anal cancer

Cervical cancer

Cisplatin is effective as a radiosensitiser

6-8 mg/m2 daily

30 mg/m2 weekly

70 mg/m2 3-weekly

Concomitant Chemo- and Radiotherapy


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Concomitant CT-RT: EORTC Trial B)

  • Schaake-Koning C. NEJM 1992;326:524

    331 patients randomised to one of three regimens:

    • RT alone: 30 Gy in 10 fractions, 3-week rest period,

      25 Gy in 10 fractions

    • RT + daily cisplatin (6-8 mg/m2)

    • RT + weekly cisplatin (30 mg/m2)


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EORTC Trial: Results B)

2-year Survival

  • RT alone: 13%

  • RT + daily cisplatin: 26%

  • RT + weekly cisplatin: 18%

    Schaake-Koning C. NEJM 1992;326:524


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Sequential versus concomitant CT-RT B)

  • Japanese study:Furuse K et al. JCO 1999;17:2692

    n= 320 MS (mo) 5y-DFS

    -2 cycles MVC  RT 56 Gy 13.3 19%

    -MCV/RT-10 days rest-MVC/RT 16.5 27%

  • RTOG 9410: Curran WJ. ASCO 2003;22:a621

    n=611

    2xCVRT(60Gy) vs CV/RT OS: 4 vs 25% p= 0.046


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Neoadjuvant Therapy B)

  • Pancoast`s tumor, vertebral invasion

    • Combined neoadjuvant CT-RT should be considered

  • Tumors with ipsilateral mediastinal spread (N2)

    • Poor survival with surgery alone

    • 2 small randomised trials showed a benefit of neoadjuvant combined CT-RT

    • Roth et al. JNCI 1994;86:673

    • Phase II trials report good results of neoadjuvant CT§


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SAKK Studies B)

  • SAKK 16/00

    • Preoperative CRT vs CT in NSCLC stage IIIA

    • CT: 3 cycles docetaxel and cisplatin (D1,22,43)

    • RT: 3 weeks of RT (44 Gy in 22 fractions)

  • SAKK 16/01

    • Preoperative CRT in NSCLC pts with operable stage IIIB disease

    • The same regimen as 16/00


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Metastasis B)

40-50% at diagnosis

70% during follow-up


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Old agents B)

Cisplatin

Carboplatin

Etoposid

Vinblastin

New agents

Docetaxel

Paclitaxel

Vinorelbine

Gemcitabine

Irinotecan

Chremotherapy for NSCLC


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Regimes B)

Cisplatin+Paclitaxel

Cisplatin+Gemcitabine

Cisplatin+Docetaxel

Carboplatin+paclitaxel

Results (n=1155 pts.)

Response rate 19%

Median survival 8 months

1-year survival 33%

2-year survival 11%

Schiller et al. NEJM 2002;346:92

NSCLC: chemotherapy combinations


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New agents: B) Induction CT followed by concomitant CT-RT

Induction (2 cycles) Concomitant (2 cycles)

Vinorelbine 25 mg/m2 D1,8,(15) 15 mg/m2 D1,8

Cisplatin 80mg/m2 D1 80mg/m2 D1

Paclitaxel 225 mg/m2 D1 135 mg/m2 D1

Cisplatin 80mg/m2 D1 80mg/m2 D1

Gemcitabine 1250 mg/m2 D1,8 600 mg/m2 D1,8

Cisplatin 80mg/m2 D1 80mg/m2 D1

CALGB study 9431: Vokes et al. JCO 2002;20:4191


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New agents: B) Induction CT followed by concomitant CT-RT

RR(CT) RR(CT-RT) 1yS 2yS 3yS

(%)

V+C 44% 73% 65 40 23

P+C 33% 67% 62 29 19

G+C 40% 74% 68 37 28

CALGB study 9431: Vokes et al. JCO 2002;20:4191


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Conclusion: B) Combined-Modality Therapy for Stage III Disease

  • Adding CT to radiation therapy improves survival and alters the course of this disease

  • Phase III studies suggest improvement in both local control and survival with concomitant CT-RT

  • Combined CT-RT should be the standard of care of patients with good PS and minimal weight loss

  • The absolute gain from combined CT-RT is still modest

  • The role of surgery following induction CT-RT is for patients with unresectable Cancer is being explored


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Small-cell Lung Cancer B)(SCLC)

  • 15-20% of all lung cancer

  • Incidence: 15/100000/year

  • Men : women = 5 : 1


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SCLC B)

  • Rapid local and metastatic spread

  • Mediastinal lymph node metastasis in most cases

  • Median Survival in untreated patients 2-3 months

  • Superior vena caval obstruction and paraneoplastic syndromes (SIADH, Cushing)

  • Association with smoking


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Limited Disease B)

Confined to:

One hemithorax

Mediastinum

Ipislateral hilar and supraclavicular nodes

Extensive Disease

Malignant pleura and pericard effusion

Contralateral hilar and supraclavicular nodes

SCLC Staging


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SCLC Therapy B)

  • No surgery; SCLC is a systemic disease

  • Chemotherapy is the standard of care

    • Cisplatin+Etoposid

  • Limited stage SCLC: Bimodality therapy with chemotherapy and radiotherapy


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SCLC Therapy B)

  • The addition of thoracic RT significantly improves survival in patients with LS-SCLC

    • Meta-analysis. Pignon et al. NEJM 1992;327:1618

    • 14% reduction in the mortality rate

    • 5.4% benefit in terms of OS at 3 years

  • Early use of RT with CT improves cure rates


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SCLC Therapy B)

  • The actuarial risk of CNS metastasis developing 2 years after CR of SCLC is 35%-60%

  • Prophylactic cranial Irradiation is recommended for pts. With LS-SCLC in CR

    • Meta-analysis: Auperin et al. NEJM;1999:341:475

    • PCI: 5.4% greater absolute survival at 3 years


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SCLC Results B)

  • Limited Disease:

    • Remission rate 80-90%

    • CR 50-60%

    • Median Survival 18-20 months

    • 2-year Survival 40%

    • 5-year Survival 15-25%


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SCLC Results B)

  • Extensive Disease:

    • Remission rate 70-80%

    • CR 20-30%

    • Median Survival 8-10 months

    • 2-year Survival < 10%


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